一种肿瘤靶向IL-12免疫细胞因子疗法可增加晚期实体瘤患者外周中具有与增强肿瘤细胞裂解相关表型的自然杀伤（NK）细胞

Background: PDS01ADC (previously designated NHS-IL12) is a tumor-targeting immunocytokine with promising preclinical activity. A first-in-human clinical trial (NCT01417546) showed PDS01ADC monotherapy to be safe and well tolerated in patients with advanced solid malignancies, and preliminary signs of clinical activity (stable disease in 50% of evaluable patients) were observed. Here, we investigate peripheral blood natural killer (NK) cell phenotypes that associate with tumor cell lysis in ex-vivo assays, and evaluate patients treated with PDS01ADC for changes in these NK phenotypes and for correlations with clinical response. Methods: Healthy donor NK cells (n=12) were evaluated in lysis assays with human SW620 colorectal and H69 small cell lung cancer tumor cells and assessed by flow cytometry. Peripheral blood collected from patients with advanced malignancies before and after 2 and 4 weeks of PDS01ADC treatment (n=28) was also assessed for changes in NK cell phenotypes and for correlations with response. Results: Total NK cells were not changed upon PDS01ADC treatment; however, several NK cell phenotypes that positively associated with NK cytotoxicity were increased after treatment. For example, Granzyme B + NK cells positively correlated with NK cell lysis of SW620 tumor cells (p=0.0299, r=0.6364) and were increased with PDS01ADC treatment (p<0.0001). A more refined phenotype of NK cells, co-expressing both cytotoxic molecules and activating receptors (Granzyme B + Perforin + NKG2D + NKp46 + ), showed a stronger correlation with NK cell lysis (p=0.0002, r=0.9021), and was both increased in patients upon PDS01ADC treatment and associated with clinical response (p=0.0688). Other refined NK subsets expressing inhibitory receptors, such as NKG2A + TIGIT + Perforin + NK cells, negatively correlated with lysis (p=0.0078, r=-0.7413), and were decreased with PDS01ADC, with greater decreases associated with improved clinical response (p=0.0224). Conclusions: PDS01ADC increased peripheral NK cells with specific phenotypes that positively associated with tumor cell lysis, with increases in some cases correlating with clinical response. These findings highlight the importance of deep interrogation of the peripheral immunome and demonstrate the role of NK cells in the biologic activity of PDS01ADC. Studies combining PDS01ADC with other agents to synergize with these NK cell changes are warranted.